APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease

Zonghua Li, Francis Shue, Na Zhao, Mitsuru Shinohara, Guojun Bu

Research output: Contribution to journalReview articlepeer-review

3 Scopus citations


Investigations of apolipoprotein E (APOE) gene, the major genetic risk modifier for Alzheimer’s disease (AD), have yielded significant insights into the pathogenic mechanism. Among the three common coding variants, APOE*ε4 increases, whereas APOE*ε2 decreases the risk of late-onset AD compared with APOE*ε3. Despite increased understanding of the detrimental effect of APOE*ε4, it remains unclear how APOE*ε2 confers protection against AD. Accumulating evidence suggests that APOE*ε2 protects against AD through both amyloid-β (Aβ)-dependent and independent mechanisms. In addition, APOE*ε2 has been identified as a longevity gene, suggesting a systemic effect of APOE*ε2 on the aging process. However, APOE*ε2 is not entirely benign; APOE*ε2 carriers exhibit increased risk of certain cerebrovascular diseases and neurological disorders. Here, we review evidence from both human and animal studies demonstrating the protective effect of APOE*ε2 against AD and propose a working model depicting potential underlying mechanisms. Finally, we discuss potential therapeutic strategies designed to leverage the protective effect of APOE2 to treat AD.

Original languageEnglish (US)
Article number63
JournalMolecular neurodegeneration
Issue number1
StatePublished - Dec 1 2020


  • Alzheimer’s disease
  • Amyloid-β
  • Apolipoprotein E2
  • Cerebrovascular disease
  • Lipid metabolism
  • Longevity
  • Neurofibrially tangles
  • Neuroinflammation
  • TDP-43
  • α-Synuclein

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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